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(Circulation. 2002;106:1229.)
© 2002 American Heart Association, Inc.

Clinical Investigation and Reports

Perceived Mental Stress and Mortality From Cardiovascular Disease Among Japanese Men and Women

The Japan Collaborative Cohort Study for Evaluation of Cancer Risk Sponsored by Monbusho (JACC Study)

Hiroyasu Iso, MD; Chigusa Date, MD; Akio Yamamoto, MD; Hideaki Toyoshima, MD; Naohito Tanabe, MD; Shogo Kikuchi, MD; Takaaki Kondo, MD; Yoshiyuki Watanabe, MD; Yasuhiko Wada, MD; Teruo Ishibashi, MD; Hiroshi Suzuki, MD; Akio Koizumi, MD; Yutaka Inaba, MD; Akiko Tamakoshi, MD; Yoshiyuki Ohno, MD, JACC Study Group^*

From the Department of Public Health Medicine (H.I.), Institute of Community Medicine, University of Tsukuba, Ibaraki, Japan; the Department of Public Health (C.D.), Osaka City University Medical School, Osaka, Japan; the Department of Epidemiology (A.Y.), Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan; the Department of Public Health/Health Information Dynamics (H.T., T.K.) and the Department of Preventive Medicine/Biostatistics and Medical Decision Making (A.T., Y.O.), Field of Social Science, Program in Health and Community Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan; the Department of Community Preventive Medicine (N.T.), Niigata University Graduate School of Medicine and Dental Sciences, Niigata, Japan; the Department of Public Health (S.K.), Aichi Medical University, Wakayama, Japan; the Department of Social Medicine and Cultural Sciences (Y. Watanabe), Research Institute for Neurological Diseases and Geriatrics, Kyoto Prefectural University of Medicine, Kyoto, Japan; the Department of Hygiene (Y. Wada), Hyogo College of Medicine, Hyogo, Japan; Asama General Hospital (T.I., H.S.), Saku, Nagano, Japan; the Department of Health and Environmental Sciences (A.K.), Graduate School of Medicine, Kyoto University, Kyoto, Japan; and the Department of Public Health (Y.I.), Juntendo Medical University, Tokyo, Japan.

Reprint requests to Prof Hiroyasu Iso, MD, Department of Public Health Medicine, Institute of Community Medicine, University of Tsukuba, 1-1-1 Tennodai, Tuskuba-shi, Ibaraki-ken 305-3785, Japan.

	Abstract

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Background— Perceived mental stress has been associated with risk of coronary heart disease (CHD) in white men, but no prospective data are available for other ethnic groups.

Methods and Results— From 1988 to 1990, a total of 73 424 Japanese (30 180 men and 43 244 women), aged 40 to 79 years, without a history of stroke, CHD, or cancer completed a lifestyle questionnaire including perception of mental stress under the Japan Collaborative Cohort Study for Evaluation of Cancer Risk Sponsored by Monbusho (JACC Study). Systematic surveillance was completed until the end of 1997, with a 580 378 person-year follow-up, and the underlying causes of death were determined according to the International Classification of Diseases, 10th revision. For women, there were 316 with total stroke, 113 with CHD, and 643 with total cardiovascular disease (CVD); for men, there were 341, 168, and 778, respectively. Women who reported high stress had a 2-fold higher age-adjusted risk of mortality from total stroke and CHD and 1.5-fold higher risk of total CVD compared with those who reported low stress. Further adjustment for known cardiovascular risk factors and selected psychological variables did not alter the associations materially. The multivariate relative risk for women who perceived high stress versus low stress was 2.24 (95% CI 1.52 to 3.31, P<0.001) for total stroke, 2.28 (95% CI 1.17 to 4.43, P=0.02) for CHD, and 1.64 (95% CI 1.25 to 2.16, P<0.001) for total CVD. For men, these relations were generally weaker but suggestive of myocardial infarction.

Conclusions— Perceived mental stress was associated with increased mortality from stroke for women and with CHD for men and women.

Key Words: stress • mortality • stroke • myocardial infarction • follow-up studies

	Introduction

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Mental stress is considered a risk factor for cardiovascular disease (CVD) according to experimental and clinical evidence.¹ Mental stress may cause increased sympathetic activity, which could lead to increased ambulatory blood pressure levels and pulse rates,² reduced insulin sensitivity,³ increased platelet aggregation,⁴ and endothelial dysfunction.⁵ These effects, individually or in combination, may contribute to increased risk of CVD.

Furthermore, mental stress is a common trigger of myocardial ischemia during routine activities of daily living among patients with stable coronary heart disease and/or silent exercise-induced myocardial ischemia.⁶ Mental stress can cause coronary vasoconstriction at sites with atherosclerotic plaques.⁷ These findings suggest that mental stress may trigger the clinical events of coronary heart disease, particularly in the presence of advanced coronary atherosclerosis.

However, there are limited epidemiological data on the relationship between mental stress and mortality as well as the incidence of CVD. Previous case-control studies have suggested a possible role for perceived mental stress on the occurrence of myocardial infarction⁸ and sudden death,⁹ but the findings were liable to recall bias due to the study design. A prospective study, with an advantageous study design, showed positive correlation between perceived mental stress and the incidence of coronary heart disease among white men.¹⁰ To our knowledge, there is no prospective evidence on the risk of coronary heart disease among nonwhite populations or on the risk of stroke in either whites or nonwhites. We examined the relationship between perceived mental stress and mortality due to stroke, coronary heart disease, and total CVD among Japanese men and women in a large cohort study.

	Methods

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The Japan Collaborative Cohort Study for Evaluation of Cancer Risk Sponsored by Monbusho (JACC Study) began in 1988 to 1990, when 110 792 individuals (46 465 men and 64 327 women) aged 40 to 79 years and living in 45 communities across Japan participated in municipal health screening examinations and completed self-administered questionnaires about their lifestyles and medical histories of previous CVD and cancer.¹¹ Informed consent was obtained from them when they completed the questionnaire. Among them, 32 184 men and 45 876 women provided a valid response (extremely high, high, medium, or low) to the question about awareness of stress: "What is the level of stress in your daily life?" We excluded 2004 men and 2652 women from the analysis because of a previous history of stroke, coronary heart disease, or cancer at baseline. Therefore, 30 180 men and 43 244 women were enrolled in the present study.

Mortality Surveillance
For mortality surveillance in each community, investigators conducted systematic review of death certificates, all of which were forwarded to the public health center in the area of residency. Mortality data were sent centrally to the Ministry of Health and Welfare, and the underling causes of death were coded according to the International Classification of Diseases, 10th Revision, for the National Vital Statistics. Registration of death is required by the Family Registration Law in Japan and is believed to be followed across Japan. Therefore, all deaths that occurred in the cohort were ascertained by death certificates from a public health center, except for subjects who died after they had moved from their original community, in which case the subject was treated as a censored case. The follow-up was conducted until the end of 1997, and the average follow-up period for the participants was 7.9 years. The present study was approved by the Ethics Committee of the Nagoya University School of Medicine.

Statistical Analysis
Statistical analyses were based on sex-specific incidence rates of stroke during the follow-up period from 1989 to 1997. For each participant, the person-years of follow-up were calculated from the date of filling out the baseline questionnaire to death, moving out of the community, or the end of 1997, whichever was first. The sex-specific relative risk of mortality from CVD was defined as the death rate among participants in 3 categories of awareness levels of mental stress divided by the corresponding rate among those with low mental stress. The percent distributions of the response was 17% for low stress, 61% for medium stress, 11% for high stress, and 11% for extremely high stress among men, and the respective values for women were 17%, 63%, 95%, and 11%. Because of the relatively low percentages of the categories of high and extremely high stress, these 2 categories were combined.

Age-adjusted means and proportions of selected cardiovascular risk factors and psychological factors were presented among the categories of perceived mental stress; statistical testing was not conducted because of the large sample size. The age-adjusted and multivariate-adjusted relative risks and their 95% CIs were calculated after adjustment for age and potential confounding factors by using the Cox proportional hazards model. These confounding variables included body mass index (sex-specific quintiles), smoking status (never, exsmoker, and current smokers of 1 to 19 and 20 cigarettes per day), alcohol intake category (never, exdrinker, and current drinkers of ethanol at 1 to 22, 23 to 45, 46 to 68, and 69 g per day), hours of walking (<1, 1 to 2, 3 to 4, and 5 hours per week), and hours of sleep (<6.0, 6.0 to 6.9, 7.0 to 7.9, 8.0 to 8.9, and 9.0 hours per day). In addition, histories of hypertension and diabetes were included in the multivariate model as intermediate variables to examine how the inclusion of these variables influenced the association between mental stress and the risk of CVD. Furthermore, psychological variables other than perceived mental stress were included as dummy variables of responses in the multivariate models. These variables were (1) hopelessness (definitely yes, yes, maybe yes, or no), which was based on the following question: "Do you have some hope in your daily life?"; (2) self-estimation of quick response (yes, maybe yes, or no), which was based on the following question: "Do you have a quick response to things you need to deal with?"; (3) sense of hurry (definitely yes, yes, maybe yes, or no), which was based on the following question: "Are you in a hurry to achieve your jobs?"; (4) anger (yes, maybe yes, or no), which was based on the following question: "Are you likely to be angry?"; (5) joyfulness (definitely yes, yes, maybe yes, or no), which was based on the following question: "Do you enjoy your life?"; (6) fulfillment (definitely yes, yes, maybe yes, or no), which was based on the following question: "Do you wish to have your life again?"; and among those persons with full-time jobs, (7) job stress (yes or no), which was based on the following question: "Do you have difficulty in relations with other persons at job sites?" and (8) job control (yes or no), which was based on the following question: "Do you have a sense of control for job demand?"

Cause-specific mortality was determined by total stroke (International Classification of Diseases, 10th revision, codes I60 to I69), total coronary heart disease (codes I20 to I25), myocardial infarction (code I21), and total CVD (codes I01 to I99) separately. Further grouping of total strokes was conducted as subarachnoid hemorrhage (code I60), intraparenchymal hemorrhage (code I61), and ischemic stroke (code I63). We conducted stratified analyses by age (40 to 64 years and 65 years), history of hypertension (no versus yes), and history of diabetes (no versus yes) to assess the effect of modification, and the presence of interaction was tested by using cross-product terms of mental stress variables and stratified variables.

	Results

Top Abstract Introduction Methods Results Discussion Appendix References

 
Among 30 180 men and 43 244 women followed up for 7.9 years, 778 men and 643 women died from total CVD. These deaths among men included 341 total strokes (95 intraparenchymal hemorrhages, 40 subarachnoid hemorrhages, and 129 ischemic strokes) and 168 coronary heart diseases (133 myocardial infarctions). The respective number of deaths among women was 316 (66, 78, and 99) and 113 (89).

Table 1 shows sex-specific selected cardiovascular risk factors and psychological factors by 3 categories of perceived mental stress. Compared with men and women who reported low mental stress, those who reported higher stress were 1 to 7 years younger, more educated, more sedentary, and more likely to have a history of hypertension or diabetes and full-time work, and they had lower mean values of body mass index and ethanol intake, and, for women, smoked more.

View this table: [in this window] [in a new window]   Table 1. Sex-Specific Age-Adjusted Mean Values or Prevalence of Cardiovascular Risk Factors at Baseline According to Perceived Mental Stress

Grades of perceived mental stress were positively associated with anger, hurry, no fulfillment, and, among full-time workers, job stress, whereas they were inversely associated with job control for both sexes. The proportions of no quick response, hopelessness, no joyfulness, and not being trusted were lower among persons with medium stress and higher among persons with high stress compared with those with low stress.

Table 2 shows sex-specific age-adjusted and multivariate relative risks of total stroke and stroke subtypes, total coronary heart disease, myocardial infarction, and total CVD. Compared with women who reported low mental stress, women with high mental stress had 2 times higher age-adjusted mortality from total stroke and coronary heart disease and 1.6 times higher mortality from total CVD. The excess mortality was particularly evident for intraparenchymal hemorrhage and myocardial infarction. We found significant multivariate relative risks (95% CI) after adjustment for potential cardiovascular factors other than hypertension and diabetes among women as follows: 2.10 (1.45 to 3.02), P<0.001 for total stroke; 3.69 (1.43 to 9.54), P=0.007 for intraparenchymal hemorrhage; 2.13 (1.00 to 4.54), P=0.05 for subarachnoid hemorrhage; 2.20 (1.17 to 4.12), P=0.01 for ischemic stroke; 2.20 (1.19 to 4.08), P=0.01 for coronary heart disease; 2.66 (1.32 to 5.34), P=0.006 for myocardial infarction; and 1.64 (1.27 to 2.12), P<0.001 for total CVD. Further adjustment for hypertension and diabetes somewhat attenuated these relations, but they remained statistically significant. The adjustment for selected psychological factors did not alter these relations materially and made the relation with subarachnoid hemorrhage even stronger. The multivariate relative risk (95% CI) of subarachnoid hemorrhage was 2.71 (1.21 to 6.09), with P=0.02.

View this table: [in this window] [in a new window]   Table 2. Sex-Specific Age-Adjusted and Multivariate RRs and 95% CIs of Mortality From Stroke, Coronary Heart Disease, and Total Cardiovascular Disease According to Perceived Mental Stress

Men with high mental stress showed no significant excess risks of mortality from total stroke, stroke subtypes, coronary heart disease, myocardial infarction, or total CVD. For myocardial infarction, a significant excess risk was found among men with medium mental stress, and the risk tended to be higher among men with high mental stress. The multivariate relative risks of myocardial infarction (95% CI) among men with medium or high mental stress compared with those with low mental stress were, respectively, as follows: 1.74 (1.05 to 2.90), P=0.03 after adjustment for cardiovascular risk factors; and 1.66 (0.99, 2.81), P=0.06 after further adjustment for psychological factors (not shown).

Multivariate relative risks of CVD were examined for men and women combined, further stratifying by 2 age groups (40 to 64 and 65 to 79 years), hypertension, and diabetes status (Table 3). The excess risk of mortality due to total stroke and total CVD tended to be more evident among hypertensive and diabetic individuals, and the interaction of stress with diabetes for total CVD was of borderline statistical significance (P=0.06). The excess risk of mortality due to total stroke and coronary heart disease tended to be more evident among the older age group, and the interaction of stress with age for total stroke was of borderline statistical significance (P=0.07).

View this table: [in this window] [in a new window]   Table 3. Multivariate RRs and 95% CIs of Mortality From Stroke, Coronary Heart Disease, and Total Cardiovascular Disease

	Discussion

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In the present large prospective study of middle-aged Japanese men and women, we observed excess mortality from total stroke, myocardial infarction, and total CVD associated with perceived mental stress. The excess risk of mortality associated with high mental stress was particularly evident among women and was still statistically significant after adjustment for known cardiovascular risk factors. For men, the significant excess risk associated with medium and high mental stress was observed for myocardial infarction.

The excess risk of myocardial infarction or coronary heart disease associated with perceived mental stress among Japanese men and women was similar to that reported previously for middle-aged white individuals.¹⁰ In a prospective study of Swedish men, however, perceived mental stress was related to the risk of uncomplicated angina pectoris but not to the risk of complicated angina leading to myocardial infarction.¹² Another prospective study of Swedish women showed that the degree of strain experience (subjective feelings of stress) was associated with risk of angina pectoris but failed to show any significant excess mortality from coronary heart disease.¹³ Furthermore, the Framingham study failed to show any significant relationship between perceived daily stress and risk of coronary heart disease for either sex.¹⁴

The present study also showed that perceived high mental stress was associated with risk of mortality from total stroke (each of intraparenchymal hemorrhage, subarachnoid hemorrhage, and ischemic stroke) among Japanese women. To our knowledge, this is the first report involving the prospective association between mental stress and mortality from stroke (either hemorrhagic or ischemic).

The reason for stronger associations of mental stress with CVD among women than among men is uncertain. There may a great deal of fluctuation in life stress and also intraindividual variability in perceived mental stress. Therefore, a simple question in the present study is likely to have a high degree of exposure misclassification, which makes the association between mental stress and the risk approach null. It is possible that the long-term variability of perceived mental stress may be less among women than among men because of less opportunity of having job stress; the percentage of having a full-time job at baseline was 75% among men and 32% among women. There was another possibility that men were inclined not to admit having high mental stress, which was supported by the fact that the distribution of mental stress was similar between men and women although more than twice as many men were employed full time. The residual confounding by job-related factors among men was not negated because we had limited data on job stress and control for the statistical adjustment.

One of the potential mechanisms of the excess risk of stroke and myocardial infarction associated with mental stress is the effect of the latter on increased ambulatory blood pressure levels and heart rates though increased sympathetic nervous activities.² Hypertension and tachycardia raise the risk of stroke and coronary heart disease.¹⁵ Exaggerated blood pressure response to mental stress was associated with increased intima-media thickness in carotid arteries¹⁶ and with subsequent progression of carotid atherosclerosis.¹⁷ In the present study, the prevalence of history of hypertension was higher with increased mental stress for both sexes. A stronger relation of mental stress with intraparenchymal hemorrhage than with ischemic stroke and coronary heart disease supports this mechanism inasmuch as hypertension is a stronger risk factor for intraparenchymal hemorrhage.¹⁸

The effect of mental stress on increased glucose intolerance or insulin insensitivity³ is another possible mechanism for the observed mortality. In the present study, the prevalence of a history of diabetes was higher with increased mental stress for both sexes. Diabetes raises the risk of ischemic stroke and coronary heart disease.^19,20 These findings suggest that the excess risk associated with mental stress may be mediated by hypertension and diabetes. However, adjustment for hypertension and diabetes did not eliminate the excess risk, suggesting other mechanisms.

Mental stress is a common trigger of myocardial ischemia during routine activities of daily living⁶ as well as during psychological tests²¹ among patients with stable coronary heart disease and/or silent exercise-induced myocardial ischemia. The development of coronary vasoconstriction has been demonstrated in areas of atherosclerotic plaques after mental stress.⁷ These findings suggest that mental stress may trigger the clinical events of coronary heart disease when coronary atherosclerosis is advanced. This implication was supported by our present finding that the excess mortality from coronary heart disease associated with mental stress tended to be more evident among older individuals and those with hypertension who may have more advanced atherosclerosis compared with younger people and those with normal blood pressure.

Increased platelet aggregability due to mental stress⁴ is also a plausible mechanism. In this regard, increased platelet aggregability raises the risk of ischemic stroke and coronary heart disease.²²

The prolonged impairment of endothelium-dependent relaxation potentially caused by mental stress⁵ is a plausible mechanism. Animal experimental studies suggest that endothelial dysfunction may enhance atherosclerosis through reduced availability of NO, increased vascular tone, enhanced adhesion of leukocytes, and enhanced platelet aggregation.^23,24

Limitations of the present study warrant discussion. We used a single simple question about self-perceived mental stress rather than scores of mental stress. Negative emotions, including anger,²⁵ hostility,^14,26 anxiety,²⁷ depression,^28,29 and hopelessness,³⁰ which have been associated with the incidence of or mortality from coronary heart disease and stroke, might mediate the association between perceived mental stress and CVD. We asked simple independent psychological questions about anger, hurry, self-estimation of quick response, hopelessness, sense of joyfulness, being trusted, and fulfillment. In the present study, perceived mental stress was positively correlated with anger, with hurry, and with no fulfillment for both sexes but was not consistently associated with no quick response, with hopelessness, with no joyfulness, or with not being trusted. The adjustment for these psychological factors did not alter the relationships between perceived mental stress and cardiovascular mortality.

The second limitation is the residual confounding on the association between mental stress and risk of CVD. Although we adjusted for selected cardiovascular risk factors and psychological factors, we cannot exclude the possible influence of other risk factors, lifestyles, and psychosocial factors. Third, we used the mortality data as end points, which may lead to misclassification in the diagnosis of stroke subtypes in particular. However, a widespread use of CT among local hospitals since the 1980s has probably made a death certificate diagnosis of stroke subtypes sufficiently accurate.^31,32

Fourth, differential censoring among mental stress categories may affect the results because we treated subjects who moved from their original community as a censored case. In the present study, the proportion of subjects who moved out was 2.2% in the low-stress category, 2.3% in the medium-stress category, and 4.0% in the high-stress category among men (P for difference<0.001), and the respective proportion among women was 2.9%, 2.5%, and 3.5% (P<0.001). Therefore, the relationships between mental stress and mortality may be underestimated, and the real associations would be even stronger than reported in the present study.

The strength of the present study is the high statistical power to detect moderate effects of mental stress on mortality from CVD. We found significant associations of mental stress with mortality from stroke among women and with mortality from myocardial infarction among both men and women. In conclusion, the present study provides epidemiological evidence that perceived mental stress has the potential effect of increasing the risk of stroke and coronary heart disease. Although the underlying mechanisms are not well established, individuals with high mental stress should be regarded as a high-risk group for stroke among women, and as a high-risk group for coronary heart disease among men and women.

	Acknowledgments

 
This work was supported by a Grant-in-Aid for Scientific Research (Nos. 61010076, 62010074, 63010074, 1010068, 2151065, 3151064, 4151063, 5151069, 6279102, and 11181101) from the Ministry of Education, Science, Sports, and Culture of Japan. The authors express their sincere appreciation to Dr Kunio Aoki, former chairman of the JACC Study Group and Professor Emeritus, Nagoya University School of Medicine, and also to Dr Haruo Sugano, former Director of the Cancer Institute of the Japanese Foundation for Cancer Research, who greatly contributed to the initiation of the study. We thank Dr Ichiro Kawachi, Harvard University, and Dr Hideto Takahashi, University of Tsukuba, for their valuable scientific suggestions.

	Footnotes

 
*The Japan Collaborative Cohort Study for Evaluation of Cancer Risk Sponsored by Monbusho (JACC Study) Group is listed in the Appendix.

	Appendix

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Present Members of JACC Study and Affiliations
The present members of the JACC Study and their affiliations are as follows: Dr Yoshiyuki Ohno (present chairman of the study group), Nagoya University Graduate School of Medicine; Dr Mitsuru Mori, Sapporo Medical University School of Medicine; Dr Yutaka Motohashi, Akita University School of Medicine; Dr Shigeru Hisamichi, Tohoku University Graduate School of Medicine; Dr Yosikazu Nakamura, Jichi Medical School; Dr Hiroyasu Iso, Institute of Community Medicine, University of Tsukuba; Dr Haruo Mikami, Chiba Cancer Center; Dr Shuji Hashimoto, School of Health Sciences and Nursing, University of Tokyo; Dr Yutaka Inaba, Juntendo University School of Medicine; Dr Yoshiharu Hoshiyama, Showa University School of Medicine; Dr Hiroshi Suzuki, Niigata University School of Medicine; Dr Hiroyuki Shimizu, Gifu University School of Medicine; Dr Hideaki Toyoshima, Nagoya University Graduate School of Medicine; Dr Akiko Tamakoshi, Nagoya University Graduate School of Medicine; Dr Shinkan Tokudome, Nagoya City University Medical School; Dr Yoshinori Ito, Fujita Health University School of Health Sciences; Dr Akio Koizumi, Graduate School of Medicine and Faculty of Medicine Kyoto University; Dr Takashi Kawamura, Kyoto University Center for Student Health; Dr Yoshiyuki Watanabe, Kyoto Prefectural University of Medicine, Research Institute for Neurological Diseases and Geriatrics; Dr Masahiro Nakao, Kyoto Prefectural University of Medicine; Dr Chigusa Date, Osaka City University Medical School; Dr Takaichiro Suzuki, Research Institute, Osaka Medical Center for Cancer and Cardiovascular Diseases; Dr Tsutomu Hashimoto, Wakayama Medical University; Dr Takayuki Nose, Tottori University Faculty of Medicine; Dr Norihiko Hayakawa, Research Institute for Radiation Biology and Medicine, Hiroshima University; Dr Takesumi Yoshimura, Institute of Industrial Ecological Sciences, University of Occupational and Environmental Health, Japan; Dr Katsuhiro Fukuda, Kurume University School of Medicine; Dr Naoyuki Okamoto, Kanagawa Cancer Center; Dr Teruo Ishibashi, Asama General Hospital; Dr Hideo Shio, Shiga Medical Center; Dr Tomoyuki Kitagawa, Cancer Institute of the Japanese Foundation for Cancer Research; Dr Toshio Kuroki, Gifu University; and Dr Kazuo Tajima, Aichi Cancer Center Research Institute.

Past Investigators
The past investigators of the study group are listed in Ohno et al, ¹¹ except for the following 2 members (affiliations are institutions where they participated during the study): Dr Takashi Shimamoto, Institute of Community Medicine, University of Tsukuba, and Dr Heizo Tanaka, Medical Research Institute, Tokyo Medical and Dental University.

Received March 26, 2002; revision received June 17, 2002; accepted June 18, 2002.

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